Action Points

With an ASCVD risk threshold of 7.5%, the incremental cost-effectiveness ratio was $37,000/QALY when compared to a threshold of 10% or higher, but there is a very high chance that the optimal ASCVD threshold is 5.0% or lower using a cost-effectiveness threshold of $100,000/QALY.

A pair of studies reported in JAMA bolster the case for statins in primary prevention of myocardial infarction and stroke, even among low risk individuals.

But the likelihood that these studies will quell debate about the benefit and cost-effectiveness of statin therapy in a relatively healthy population is unlikely.

The two papers used different methods to arrive at the same conclusion.

In a sample of 2,435 statin-naive patients, Udo Hoffmann, MD, MPH, of Massachusetts General Hospital and Harvard Medical School, and colleagues, used the ACC/AHA Pooled Cohort Equation to identify patients eligible for statin therapy -- a risk score model that throws a much wider-net than the National Cholesterol Education Program's 2004 Updated Third Report of the Expect Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III) guidelines, which only identified 14% of the cohort as statin-eligible.

Hoffmann wrote that 6.3% of those who were considered statin eligible based the ACC/AHA 2013 guidelines developed incident cardiovascular disease (CVD), as did 6.9% of those who were statin eligible based on the ATP III guidelines, but among non-statin eligible participants, only 1.0% developed incident CVD based on the ACC/AHA threshold compared with 2.4% based on the ATP III threshold (P<0.001).

The second study, which made calculations with a hypothetical patient model, found that lowering the Framingham Risk Score threshold down to a 3% or 4% 10-year risk of developing atherosclerotic cardiovascular disease from the current 7.5% would yield an incremental-cost-effectiveness ratio of $81,000/quality-adjusted life-year (QALY) or $140,000/QALY, respectively, according to Ankur Pandya, PhD, of Harvard School of Public Health, and colleagues.

Pandya's group also estimated that shifting from an atherosclerotic cardiovascular disease (ASCVD) risk threshold of 7.5% to 3.0% or higher would be associated with an additional 161,560 CVD events avoided.

"Although a 10-year ASCVD risk threshold of 7.5% or higher might initially seem to be a low threshold, many, indeed most, CVD events occur among the low-risk members of the population," Philip Greenland, MD, of Northwestern University, and Michael S. Lauer, MD, of the National Heart, Lung, and Blood Institute (NHLBI), wrote in an editorial that accompanied the papers. "The vast majority of ASCVD events occur among lower-risk persons because they comprise the greatest portion of the population."

"The findings reported by Pandya et al in this issue of JAMA suggest that an even lower threshold than 7.5% 10-year CVD risk may be cost-effective," Greenland and Lauer wrote. "These findings suggest that the currently recommended threshold of 7.5% is cost-effective, and a lower threshold might also be cost-effective."

The Threshold Sweet Spot

From 2002 to 2005, Hoffmann's group began to look at the children and grandchildren of Framingham Heart Study participants, who they followed for the next 8-10 years.

The average age for the 2,435 study participants was 51.3, the average FRS was 6.7%, the average LDL-C level was 121 mg/dL, and according to the authors, "The population was overwhelmingly white."

According to Greenland and Lauer, the first three criteria for prescribing statins in the ACC/AHA guidelines have been widely accepted: patients who have ASCVD, or LDL-C levels higher than 190 mg/dL, and patients over 40 who have diabetes and LDL-C levels from 70 to 189 mg/dL.

The fourth criteria, however, has been regarded as more controversial: otherwise healthy patients ages 40 to 75 who have LCL-C levels from 70-189 mg/dL and an estimated FRS of 7.5% or higher.

The ATP III guidelines mostly mirror the first two criteria in the ACC/AHA guidelines, but patients without CVD or diabetes need to have at least LDL-C levels of 130 mg/dL and 2 risk factors or higher levels of LDL-C and fewer risk factors to qualify for statins.

These results remained constant regardless of focus on subgroup analysis in gender, diabetes status, aspirin or hypertensive therapy.

In a subanalysis of the intermediate population (FRS 6% to 20%), which was 38% of the population, 3.9% experienced incident CVD. In the intermediate group, 80% were statin-eligible based on the ACC/AHA guidelines, and 27% were based on the ATP III guidelines (P<0.001).

Baseline characteristics among the intermediate-risk group were similarly distributed between those with and without future CVD events, although coronary artery calcification (CAC) was significantly higher in those who experienced events, the authors wrote.

With the ATP III guidelines, there wasn't much of a difference between rates of CVD for those who were not statin-eligible (3.6%) and those who were (4.0%). However, with the ACC/AHA guidelines, 4.8% of statin eligible patients had incident CVD compared with 0.5% for non-eligible participants (HR 9.3, 95% CI 1.3-67.8, P=0.03).

In participants who were newly statin eligible, 24% had an incident CVD rate of 5.7%, yielding a number needed to treat (NNT) of 39 to 58.

"Extrapolating our findings to the approximately 10 million U.S. adults who are newly eligible for statins, we estimate that between 41,000 and 63,000 incident CVD events would be prevented over a 10-year period by adopting the ACC/AHA guidelines," Hoffmann and colleagues wrote.

Calculating Costs

Pandya's group developed a CVD microsimulation model, designed to predict the lifetime health outcomes and costs related to CVD events in 1 million hypothetical adults. Weighted sampling from the National Health and Nutrition Examination Surveys (NHANES), from waves beginning in 2005 through 2010, served for the cohort with baseline ages of 40 to 75.

Pandya's team estimated the number of ASCVD events that could be prevented with statin therapy, and the incremental costs per QALY gained based on a model designed with data from large clinical trials and meta-analyses of statin benefit and treatment studies.

With a threshold of 7.5% or higher, the incremental cost-effectiveness ratio was $37,000/QALY when compared to a threshold of 10% or higher. This represented 48% of patients treated.

In a sensitivity analysis, the researchers calculated that there was a higher than 93% chance that the optimal ASCVD threshold was 5.0% or lower using a cost-effectiveness threshold of $100,000/QALY.

"Assuming generic statin prices only, we projected that it would be cost-effective to treat up to 61% to 67% of adults with statins," Pandya and colleagues wrote.

And Greenland and Lauer agreed. "The Pooled Cohort Equation appears to be a justifiable approach to risk assessment as a replacement for the older Framingham Risk Score, and the recommended threshold of 7.5% is also justifiable; in fact, it may even be too conservative," they wrote.

Pursnani and colleagues reported the small number of events and lack of population diversity as limitations. Pandya and colleagues reported using pre-2006 data, calculation assumptions, and not stratifying age- or sex-specific treatment guidelines as limitations.

Weinstein reported a financial relationship with Optuminsight. Hoffmann reported a financial relationship with HeartFlow Inc., Siemens Healthcare, and Genentech. None of the other authors reported any relevant financial relationships with industry.

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